It is recognized that both genetic and environmental factors play a role in breast cancer. The genetic component has been verified by the discovery of the high-penetrance genes BRCA1 and BRCA2. Hormonal factors, radiation, diet, oral contraceptive use and estrogen replacement therapy are among some of environmental factors believed to influence breast cancer risk. Population genetic theory predicts that a large proportion of the prevalence of complex diseases will be due to genetic variation and environmental risk factors that are common in the population. Low penetrance genetic variants may not have a large influence on individual risk, however when common in the population, will be a large component of the overall attributable risk for the disease. Until recently, the interaction between environmental risk factors and genes in determining breast cancer risk has not been explored. We are now at a point where we can use the existing resource of population-based breast cancer families to characterize common genetic variants in a series of candidate breast cancer modifier genes and study the relationship between this variation, environmental risk factors and breast cancer risk. This innovative approach uses our fully characterized resource. The Specific Aims of this new phase are as follows: 1) We will, in an initial discovery phase, identify common sequence variants in a panel of candidate genes selected because of their potential function in a specific pathway known to be associated with increased risk of breast cancer or physiological changes associated with a known risk factor for breast cancer; 2) To study the relationship between a series of candidate genes and breast cancer risk; 3) To study the effects on breast cancer risk due to the environmental risk factors and the interaction between the candidate genes and environmental risk factors; 4) To validate and fine map any genetic factors which are found to influence breast cancer risk in the analyses described in Specific Aims 2 and 3.